Diversification and shared features of tumor‐binding antibody repertoires in tumor, sentinel lymph node and blood of three patients with breast cancer

Abstract

ObjectivesB cell‐mediated immunity can be associated with favorable clinical outcomes in cancer patients. However, the mechanism and features of anti‐tumor immune responses are not well understood. In particular, how B cells expressing tumor‐specific antibodies are distributed (in the tumor vs. the circulation) has not been well defined.MethodsWe performed an in‐depth analysis of B cell antibody repertoires derived from the tumor, sentinel lymph nodes and peripheral blood of three treatment‐naïve patients with breast cancer. We integrated transcriptional analysis, next‐generation sequencing of immunoglobulin heavy‐chain gene rearrangements and phage display to define B cell responses and clonal architecture in the tumor microenvironment, and to identify antibodies against autologous tumor tissues.ResultsB cell clonal lineage mapping across sequencing libraries generated from the tumor, sentinel lymph node and blood revealed that some expanded B cell clones overlap between tumor and lymph node, and fewer clones overlapped with the peripheral blood. Notably, tumor‐associated or tumor‐binding clones recovered in the phage panning and tracked back through the tissues harboured extensive somatic hypermutations in both the tumor and the lymph node.ConclusionsThese findings suggest an evolving humoral immune response that targets the tumor and the possibility of monitoring B cell clones of interest in blood after identifying them in tumor or lymph node samples. Studying the dynamics and specificity of B cell responses may provide insights into the characteristics of successful anti‐tumor immunity, provide a means for monitoring therapy and yield novel targets for personalised therapies.

IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation

“…A number of studies have demonstrated the presence of tumor-specific antibodies within the B cell repertoires of oncology patients. 9 , 10 Thus, we interrogated patient memory B cell repertoires to identify novel cancer targets using Immunome’s internal discovery platform, which combines high throughput hybridoma generation and multiplexed cell-based screening to capture the memory B cell repertoire of treatment-naïve human cancer patients. 11 , 12 Identification of antigens recognized by the patient’s humoral immune system facilitates the development of therapeutic antibodies against cancer-associated antigens on malignant cells and within the tumor microenvironment.…”